Pharmaceutical composition comprising tetrahydrocannabivarin for the prevention and treatment of overweight

ABSTRACT

The present invention relates to a pharmaceutical composition comprising a tetrahydrocannabivarin (THCV), wherein the composition further comprises cannabigerol (CBG) or cannabinodiol (CBND) or a mixture thereof, for use in the prevention and treatment of overweight, preferably associated with obesitas. The pharmaceutical composition according to the invention may further comprise the following additional compounds tetrahydrocannabinol (THC), or Cannabigerol (CBG) or Cannabinodiol (CBND) or a combination thereof.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisinga tetrahydrocannabivarin (THCV), wherein the composition furthercomprises cannabigerol (CBG) or cannabinodiol (CBND) or a mixturethereof, for the prevention and treatment of overweight includingobesity and related disorders. The present invention also relates to amethod for treating a mammal suffering from overweight or a relateddisorder, wherein a pharmaceutical composition comprising atetrahydrocannabivarin is administered to said mammal.

BACKGROUND OF THE INVENTION

Obesity, which can be defined as a body weight more than 20% above theideal body weight or even better by a Body Mass Index (BMI; expressed asthe ratio of the mammal's weight and the square of its length) of 30kg/m² or higher (cf. World Health Organization. Technical report series894: “Obesity: preventing and managing the global epidemic.”, Geneva,World Health Organization, 2000), is a rapidly increasing global problemthat urgently needs to be controlled. Obesity is the result of apositive energy balance, as a consequence of increased ratio of caloricintake to energy expenditure. The molecular factors regulating foodintake and body weight balance are incompletely understood. (B. Staelset al., J. Biol. Chem. 270(27), 15958, 1995; F. Lonnquist et al., NatureMedicine 1(9), 950, 1995). Although the genetic and/or environmentalfactors leading to obesity are poorly understood, several geneticfactors have been identified.

Obesity causes or exacerbates many health problems, both independentlyand in association with other disorders. The medical problems associatedwith obesity, which can be serious and life-threatening, includehypertension, type 2 diabetes mellitus, elevated plasma insulinconcentrations; insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast-, prostate- and colon-cancer, osteoarthritis,respiratory complications, cholelithiasis, gallstones, arteriosclerosis,heart disorder, abnormal heart rhythms, and heart arrythmias. Referenceis for example made to US 2006/276549 and WO 2006/124506 to AbbotLaboratories.

Nowadays, three medical compounds are used for the treatment of obesity,i.e. Rimonabant (Acomplia®; a CB1 cannabinoid receptor antagonist),Sibutramine (Meridia®; a neurotransmitter reuptake inhibitor) andOrlistat (Xenical®; a pancreatic lipase inhibitor). Reference is made toU.S. Pat. Nos. 6,538,034 and 4,598,089, incorporated by reference, andto the scientific articles Despres et al., “Effects of Rimonanbant onmetabolic risk factors in overweight patients with dyslipidemia”, N.Eng. J. Med, 353, 2121-2134, 2005, Despres et al., “Effects ofRimonibant on metabolic risk factors in overweight patients withdyslipidemia”, N. Eng. J. Med. 353, 2121-2134, 2005; and Li et al.,“Pharmacologic treatment of obesity”, Ann. Intern. Med. 142, 532-546,2005, all incorporated by reference. Although weight reductions of thismagnitude do produce some favourable metabolic effects, the improvementsare modest and are insufficient in treating more obese mammals.

Combinations of the pharmaceutically active agents Rimonabant,Sibutramine or Orlistat with other active components are disclosed inU.S. Pat. Nos. 7,037,944, 7,148,258, US 2005/124660, US 2006/135471, US2006/269510, US 2006/276549, US2007/060532 and US 2007/142369,incorporated by reference. However, the combinations do not seem to asignificantly greater weight reduction compared to single-drug treatment(cf. Padwal, R. S. and Majumdar, S. R., The Lancet 369, 71-77, 2007,incorporated by reference).

Studies of the weight loss medications Orlistat (Davidson, M. H. et al.,JAMA 281, 235-42, 1999), Dexfenfluramine (Guy Grand, B. et al., Lancet2, 1142-5, 1989), Sibutramine (Bray, G. A. et al. Obes. Res., 189-98,1999) and Phentermine (Douglas, A. et al., Int. J. Obes. 7, 591-5, 1983)have demonstrated a weight loss of about 5%-10% of body weight for drugcompared to placebo. In particular, Sibutramine reduces body weight byabout 10% over a 6 month or a 1 year period. Studies have also foundthat Sibutramine potently inhibits food intake and decreases body weightinitially. Studies have shown that Sibutramine reduces body weight by adual mode of action; it decreases food intake by enhancing satiety(Fantino, M. & Souquet, A.-M., Int. J. Obesity, 19, 145, 1995; Halford,J. C. G., Heal, D. J. & Blundell, J. E., Brit. J. Pharmacol. 114, 387P,1995; and Stricker-Krongrad, A., Souquet, A.-M. & Burlet, C. Int. J.Obesity, 19, 145, 1995), and it increases energy expenditure bystimulating thermogenesis (Connoley, I. P., Heal, D. J. & Stock, M. J.,Brit. J. Pharmacol. 114, 388P, 1995; and Connoley, I. P., Frost, I.,Heal, D. J. & Stock, M. J., Brit. J. Pharmacol. 117, 170P, 1996).

However medicaments such as Sibutramine and Rimonabant show adverseside-effects, e.g. dry mouth, paradoxically increased appetite, nausea,strange taste in the mouth, anorgasmia and delayed ejaculation, upsetstomach, constipation, trouble sleeping, dizziness, drowsiness,menstrual cramps/pain, headache, flushing, or joint/muscle pain.Sibutramine can substantially increase blood pressure and pulse in somepatients and “suicide” records are recently reported for Rimonabant.None of the currently used treatments for obesity is capable of fullyrelieving the symptoms in all cases. Patients frequently combinedifferent treatments in an attempt to address all of their symptoms.Clearly, although numerous treatments have been developed in an attemptto control obesity there is still a need in the art for effectivetreatments. According to the first and second aspect of the presentinvention, is to provide such a fundamental new way of treating obesityin a natural (biological) non synthetic manner.

Cannabinoids are organic compounds that are exclusively found inCannabis sativa, ruderalis, indica strains and their blends. Cannabissativa is the natural source of a set of at least 66 oxygen-containingaromatic hydrocarbon compounds that are known collectively asphytocannabinoids (ElSohly, M. A., “Chemical constituents of Cannabis,In: Grotenhermen, F. and Russo, E., editors. Cannabis and cannabinoids:Pharmacology, Toxicology and Therapeutic Potential”. Binghamton (NY):Haworth Press, 2002: 27-36). The n-propyl analogue of Δ-9tetrahydrocannabinol (THC) which was first detected in cannabis by Gillet al. (Gill, E. W., Paton, W. D. M., Pertweee, R. G., “PreliminaryExperiments on the chemistry and pharmacology of cannabis”, Nature 228,134-136, 1970) and named Δ-9 tetrahydrocannabivarin (THCV) by Merkus(Merkus, F. W. H. M., “Cannabivarin and tetrahydrocannabivarin, two newconstituents of hashish”, Nature 232, 579-580, 1971).

GB 2377633 A of GW Pharma Ltd. discloses pharmaceutical compositionscomprising cannabinoids having specific ratios of cannabidiol (CBD) totetrahydrocannabinol (THC), wherein the CBD is present in an amountgreater than the amount of THC. The compositions are clinically usefulin the treatment or management of specific diseases or medicalconditions including inflammatory diseases, diseases or conditionswherein oxidative stress plays a role, psychotic disorders, epilepsy,movement disorders, stroke, head injuries, diseases which requireappetite suppression, multiple sclerosis, spinal cord injury, peripheralneuropathy, cancer pain and migraine. The pharmaceutical compositionsmay further comprise THCV (tetrahydrocannabinovarin) and CBDV(cannabidivarin). However, Table 1 of GB 2377633 A attributes theappetite suppressing activity solely to CBD.

GB 2414933 A of GW Pharma Ltd. discloses the use of a combination ofcannabinoids for the treatment of pain, inflammation and/or diseasemodification in arthritis. The cannabinoids are selected from CBD orcannabidivarin (CBDV) and THC or tetrahydrocannabinovarin (THCV) and arein a predefined ratio by weight of less than or equal to 19:1 of CBD orCBDV to THC or THCV.

In addition, not every patient suffering from overweight is in need of asynthetic medicament or has objections against such products. There istherefore a need in the art for natural products which can be used fortreating overweight and related disorders such as obesity.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemotypes and their cannabinoid profiles.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisinga tetrahydrocannabivarin (THCV), wherein the composition furthercomprises cannabigerol (CBG) or cannabinodiol (CBND) or a mixturethereof, for use in the prevention and/or treatment of overweight. Thepresent invention further relates to a method for treating a mammalsuffering from overweight or a related disorder, wherein apharmaceutical composition comprising a tetrahydrocannabivarin (THCV),wherein the composition further comprises cannabigerol (CBG) orcannabinodiol (CBND) or a mixture thereof, is administered to saidmammal in a therapeutically effective, non-toxic amount to induce weightloss.

The present invention relates to a pharmaceutical composition comprisinga tetrahydrocannabivarin (THCV), wherein the composition furthercomprises cannabigerol (CBG) or cannabinodiol (CBND) or a mixturethereof, for the prevention and treatment of overweight. The presentinvention further relates to a method for treating a mammal sufferingfrom overweight or a related disorder, wherein a pharmaceuticalcomposition comprising a tetrahydrocannabivarin (THCV), wherein thecomposition further comprises cannabigerol (CBG) or cannabinodiol (CBND)or a mixture thereof, is administered to said mammal.

DETAILED DESCRIPTION OF THE INVENTION

The verb “to comprise” as is used in this description and in the claimsand its conjugations are used in its non-limiting sense to mean thatitems following the word are included, but items not specificallymentioned are not excluded. In addition, reference to an element by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the element are present, unless the context clearlyrequires that there is one and only one of the elements. The indefinitearticle “a” or “an” thus usually means “at least one”.

In this document, the term “tetrahydrocannabivarin” is abbreviated asTHCV. However, this term encompasses the group of compounds consistingof Δ9-tetrahydrocannabivarin, Δ8-Tetrahydrocannabivarin, and mixturesthereof. The compound Δ9-tetrahydrocannabivarin is also known as6,6,9-trimethyl-3-propyl-5″ 6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol(CAS. No. 28172-17-0). In an embodiment of the present invention,tetrahydrocannabivarin (THCV) is selected from the group consisting ofΔ9-tetrahydrocannabivarin (THCV), i8-tetrahydrocannabivarin (Δ8-THCV),and one or more mixtures thereof.

The compound Δ9-tetrahydrocannabivarin is a psychoactive cannabinoid andis found in the hemp plant Cannabis sativa. It is an analogue of THCwherein the side chain is shortened by two CH2 groups. The compoundΔ9-tetrahydrocannabivarin can be used as a marker compound todifferentiate between the consumption of hemp 10″ products and syntheticTHC. The compound Δ9-tetrahydrocannabivarin THCV is found in largestquantities from Indica strains.

Tetrahydrocannabinol (THC) is also known as(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(CAS. No. 1972-08-3). In this document, the term THC also includes 9′-or 8′-carboxylated analogs (e.g. carboxylic acids and carboxylic acidesters) thereof, e.g. 11-nor-9-carboxy-Δ9-tetrahydrocannabinol(1-hydroxy-6,6-dimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]-chromene-9-carboxylicacid; Cas. No. 64280-14-4).

Cannabigerol (CBG) is also known as(E)-2-(3,7-Dimethylocta-2,6-dienyl)-5-pentylbenzene-1,3-dial (CAS. Nos.[2808-33-5], [25654-31-3] (E); [9500-1-70-0] undefined configuration.Isomers: [25654-32-4] (Z)). CBG-analogues according to Formula 1 arelisted in Table 1.

TABLE 1 CBG-analogues according to Formula 1 Compound Cis/Trans R¹ R² R³R⁴ R⁵ Cannabigerolic cis COOH n-C₅H₁₁ H (CH₂)₂CH═C(CH₃)₂ OH acid A[(E)-CBGA-C₅ A] Cannabigerolic cis COOH n-C₅H₁₁ Me (CH₂)₂CH═C(CH₃)₂ Meacid A monomethyl ether [(E)-CBGAM-C₅ A] Cannabigerol cis H n-C₅H₁₁ H(CH₂)₂CH═C(CH₃)₂ OH [(E)-CBG-C₅] Cannabigerol cis H n-C₅H₁₁ Me(CH₂)₂CH═C(CH₃)₂ Me monomethyl ether [(E)-CBGM-C₅] Cannabigerovariniccis COOH n-C₃H₇ H (CH₂)₂CH═C(CH₃)₂ OH acid A [(E)-CBGVA-C₃ A]Cannabigerovarin cis H n-C₃H₇ H (CH₂)₂CH═C(CH₃)₂ OH [(E)-CBGV-C₃]Cannabinerolic trans COOH n-C₅H₁₁ H Me (CH₂)₂CH═C(CH₃)₂ acid A[(Z)-CBGA-C₅ A]

Cannabinodiol (CBND) is also known as2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (CAS. No. 13956-29-1). CBNDanalogues are shown in Formula 2.

As will be apparent to the person skilled in the art, one or more ofTHCV, THC, CBG and CBND may be synthetic. However, it is preferred thatthey are obtained from natural sources.

Instead of CBG, analogues may be used wherein these analogues areselected from the compounds shown above in Formula 1 and Table 1.Instead of CBND, analogues may be used wherein these analogues areselected from the compounds shown above in Formula 2.

In this document, the term “overweight” encompasses obesity and relateddisorders and metabolic syndrome related disorders. In an embodiment ofthe present invention, the use in the prevention and treatment ofoverweight is the use in the prevention and treatment of overweightassociated with obesity.

According to the invention, it is preferred that the pharmaceuticalcomposition comprises sole THCV and CBND and CBG oil. According to theinvention, it is preferred that the pharmaceutical composition (ofCannabis simplex), due to synergistic effects between THCV and THC,further comprises THC. It was found that the ratio by weight of THCV andTHC (THCV:THC) is important in which degree weight loss isinduced/appetite is reduced. In an embodiment, the ratio of THCV:THC byweight is between about 10:1 and about 1:10. In a preferred embodiment,the ratio of THCV:THC by weight is between about 1:5 and about 5:1. Inanother preferred embodiment, the ratio of THCV:THC by weight is betweenabout 1:1 and about 10:1.

A high THCV content has a beneficial effect on weight loss. It istherefore preferred that the pharmaceutical composition comprises a TCHVand THC, wherein the ratio of the THCV:THC by weight is between about10-1, more preferably about 5:1, even more preferably about 1:1.However, in all these ranges, it is preferred that the TCHV content ishigher than the THC content to avoid (unwanted) psychotropic sideeffects.

According to the invention, the pharmaceutical composition may comprisesmore than one unit which enables to administer the THCV separately,simultaneously or sequentially to THC.

In an embodiment, the composition is a unit dosage form comprising lessthan or equal to 120 mg of THCV. In an embodiment, the compositioncomprises tetrahydrocannabinol (THC) and is a unit daily dosage formcomprising less than or equal to 150 mg of THC.

According to the invention, it is preferred that the pharmaceuticalcomposition is a unit dosage form comprising less than or equal to 150mg of the THCV and higher than 1 mg of the THC.

It is furthermore preferred that the pharmaceutical composition is aunit dosage form comprising less than or equal to 150 mg of THCV in anoil formulation and higher than 1 mg of THC. Most preferable 150 mg THCVand less than 150 mg THC in oil formulations. For Cannabis simplex(medical grade) the preferred concentration range will be between 10-25%THCV and 10-25% of THC per gram of medication, wherein THCV is mostpreferably equal to or more than THC in absolute amounts.

A “unit dosage form” is to be understood as a maximum dose of medicationthat can be taken at any time or within a specified dosage period.

The unit dosage form preferably comprise a range of between about 1 andabout 150 mg of each THCV and THC in oil preparations, wherein theamount of THC is preferably in the range of between about 1 and about150 mg. More preferably, the amount of each THCV and THC in the unitdosage form is in the range of 20 to 100 mg respectively.

According to the invention, the composition further comprisesCannabigerol (CBG) or Cannabinodiol (CBND) or a mixture thereof,preferably in a ratio of THCV:CBG:CBND 10:1:5-1 10:1-5. Because CBG is atypical indica effect and actually an opposite effect of THC. Now it isknown that THC induces hunger and THCV counteracts this, by combiningthe MEB with THCV, the antagonistic action against THC will becomestronger from THCV and CBG, which causes the appetite to be suppressedmore strongly. CBND is again a catalyst that ensures that theappetite-suppressing effects can be enhanced many times over.Preferably, the composition comprises a mixture of CBG and CBND, whereinthe ratio of CBG:CBND by weight is between about 10:1 and about 1:10.

In an embodiment, the composition comprises tetrahydrocannabivarin(THCV), tetrahydrocannabinol (THC), Cannabigerol (CBG) and Cannabinodiol(CBND) in a ratio by weight of THCV:THC of between about 1:5 and about5:1 and CBG:CBND of between about 10:1 and about 1:10.

In an embodiment of the pharmaceutical composition, the compositioncomprises less than 0.10 wt. % of cannabichromene (CBC) and/orcannabinol (CBN) based on the weight of THCV. In a preferred embodiment,the composition is substantially free of CBC or substantially free ofCBN or substantially free of both CBC and CBN. In an embodiment, theratio is THCV:CBC:CBN is 10:1:1-5, 1:10: 5-1 and 1:10:5-1 10:1-5.

The pharmaceutical composition according to the present invention ispreferably packaged for delivery in a titratable dosage form. The term“titratable” is to be understood as meaning that the patient is providedwith a medication that is in such a form that smaller dosages than theunit dose can be taken. Titration of dosages in a patient relatedmanner, are beneficial to the patient as they are able to take smallerdosages of the medication until the drug is efficacious. As will beapparent to those skilled in the art, not all patients will requireexactly the same dose of medication, for example patients of a largerbuild or patients having a faster metabolism. Different patients mayalso present with different degrees of complaints and as such mayrequire larger or smaller doses in order to treat the complainteffectively. The benefits of such a dosage form over dosage forms suchas tablets, where smaller doses are difficult to take, are thereforeevident.

In an embodiment, the composition is a gel, a gel spray, a tablet, aliquid, a capsule, in a form suitable for vaporization or in a formsuitable for nebulization.

Preferably, the pharmaceutical composition according to the invention ispackaged for delivery such that delivery is targeted to an area selectedfrom one or more of the following: sublingual, buccal, oral, rectal,nasal and the pulmonary system as vapor, intravenously,intra-arterially, topically, by injection, intraperitoneally,intrapleurally, orally, subcutaneously, intramuscularly,intraepidermally, or rectally. Illustrative methods of administrationare vapor, orally and intraveneneously (IV). The oral formulations maybe solutions, suspensions, suppositories, tablets, granules, powders,capsules, ointments, or creams. The IV formulation may be solutions orsuspensions, including compositions comprising liposomes.

In the preparation of the pharmaceutical compositions according to thepresent invention, a solvent (e.g. water or physiological saline), asolubilising agent (e.g., ethanol, Polysorbates or Cremophor EL7),tonicity agents, preservatives, antioxidants, excipients (e.g. lactose,starch, crystalline cellulose, mannitol, maltose, calcium hydrogenphosphate, light silicic acid anhydride or calcium carbonate), binders(e.g. starch, polyvinylpyrrolidone, hydroxypropyl cellulose, ethylcellulose, carboxy methyl cellulose or gum Arabic), lubricants (e.g.magnesium stearate, talc or hardened oils), and stabilisers (e.g.lactose, mannitol, maltose, polysorbates, macrogols, or polyoxyethylenehardened castor oils) can be added. If necessary, glycerin,dimethylacetarnide, 70% sodium lactate, a surfactant or a basicsubstance such as sodium hydroxide, ethylenediamine, ethanolamine,sodium bicarbonate, arginine, meglumine or trisaminoethane is added.Pharmaceutical preparations such as solutions, tablets granules orcapsules can be formed with these components.

Additionally the pharmaceutical composition according to the presentinvention further comprises one or more carrier solvents. Preferably thecarrier solvents are ethanol and/or propylene glycol. Preferably theratio of ethanol to propylene and glycol is between 4:1 and 1:4. Morepreferably still the ratio is substantially 1:1.

Generally, unit dosages forms of the pharmaceutical compositionaccording to the present invention are administered in such a way thatthey provide a dosage of about 10 mg to about 200 mg, preferably about15 mg to about 150 mg, more preferably about 20 mg to about 100 mg perday of the THCV. Hence, the daily dose may include two or more unitdosage forms.

As a consequence, the present invention also relates to a pharmaceuticalcomposition for a daily dosage schedule of about 10 mg to about 200 mg,preferably about 15 mg to about 150 mg, more preferably about 20 mg toabout 100 mg of the THCV, on a Δ9-tetrahydrocannabivarin active weightbasis, wherein the pharmaceutical composition comprises one or more unitdosage forms.

The present invention also relates to a kit adapted for a daily dosageschedule of about 10 mg to about 200 mg, preferably about 15 mg to about150 mg, more preferably about 20 mg to about 100 mg of the THCV, saidkit comprising one or more unit dosage forms of a pharmaceuticalcomposition according to the present invention.

The composition according to the invention preferably has more THCV thanTHC and a bit more THCV than CBG but preferably more THC thanCBG:THCV:CBG:CBND:THC by weight is between 10:1:1-5, 1:10: 5-1.

In an embodiment, the ratio THCV:CBND is 10:1. In an embodiment, theratio THCV:CBG: is 5:1. In an embodiment, the ratio THCV:CBND:CBG is10:1:1-5 10:1-5.

FIG. 1 shows the profiles for the different chemotypes. It can be seenfrom FIG. 1 that for the present invention that type 10 and type 12 areof main interest because of the present or absent cannabinoids.

Examples Method of Preparation of Pharmaceutical Composition

Step 1: Chopping to predominantly 2-3 mm.

Step 2: Decarboxylate at 100-150° C. to form neutral forms.

Step 3: Extraction with a specific volume of Ethanol or liquid carbon.

Step 4: Removal by film-rotavoparization or depressuration of CO₂ resp.

Step 5: Winterisation: Winterisation removes unwanted components fromthe crude extract. The first step is to dilute the crude extract inethanol and store the mixture at the freezing point of ethanol (114.1°C.) for at least 24 hours. This prompts the removal of lipids and waxesfrom the extract.

Step 6: Removal of unwanted waxes by cold filtration. Filtration: Toremove precipitates and other particulates from the extract, one can usevacuum filtration via a Buchner funnel or a plate press. The filtermicron range should be 0.45 or less.

Step 7: Removal of ethanol from the filtrate by thin film evaporationunder reduced pressure, closed loop distillation. Distillation: Toproduce a cannabinoid-rich distillate product, one can either short pathdistillation, fractional distillation or wiped film distillation.

Step 8: CPC: Separating and/or purifying cannabinoids, comprising atleast one liquid-liquid partition chromatography step, or the use of acentrifugal distribution chromatograph for liquid-liquid partitionchromatography to separate and/or purify cannabinoids using a solventselected from cyclohexane, heptane, n-heptane, iso-heptane, octane,n-octane, iso-octane, which is kept stationary by centrifugal force anda second immiscible liquid phase can be pumped through as a mobilephase. More details can be found in WO2016135346A1. Fractionation ofneutral cannabinoids by CPC using the two-phase systemhexane/acetone/acetonitrile, 5:2:3 (v:v:v, solvent system 2). The CPC isoperated in ascending mode, with the lower (acetonitrile-rich) phaseused as stationary phase and the upper (hexane-rich) upper phase asmobile phase. Flow-rate set at 5 ml/min and rotation speed at 600 rpm.The volume of stationary phase at 65 ml. Dissolve the sample to a finalvolume of 5 ml of upper phase for injection. Fraction size arecollected. Analyses of fractions by TLC and further analysis by HPLC.Resulting Fraction contains a high proportion (>90%, preferably >95%) ofthe desired compound. This method is described in Hazekamp et al.,Preparative Isolation of Cannabinoids from Cannabis sativa byCentrifugal Partition Chromatography, Journal of Liquid Chromatography &Related Technologies 27(15):2421-2439-December 2004.

Step 9: One or more (desired) isolated cannabinoids are selected andcombined to be present in the pharmaceutical composition. Preferably, noother cannabinoids than the selected one(s) are present in thecomposition; however, trace amounts may be present. Preferably, theselected cannabinoids in the pharmaceutical composition are present inthe same respective weight ratios as in the Cannabis strain.

Type 3 (Indian) and Type 8 (haze type) of the chemotype chart are takenas starting material for extraction and purification. Then the purifiedrequired cannabinoids (THCV, CBG, and CBND) form at least 95 (wt.)% ofthe composition in an oil, capsule or any form.

Example 1

THCV:CBG:CBND:THC by weight is between 10:1:1-5, 1:10: 5-1 and 1:10:5-110:1-5. The effect will be a strong inhibitory action on appetite and atthe same time an energizing and boosting feeling. It will increase theantagonistic effect of this formulation on the CB1 receptor.

CLAUSES

1. Pharmaceutical composition comprising a tetrahydrocannabivarin forthe prevention and treatment of overweight.2. Pharmaceutical composition according to clause 1, wherein thetetrahydrocannabivarin is selected from the group consisting ofΔ9-tetrahydrocannabivarin, Δ8-tetrahydrocannabivarin, and mixturesthereof.3. Pharmaceutical composition according to clause 1, wherein thecomposition further comprises THC.4. Pharmaceutical composition according to clause 3, wherein thecomposition comprises a TCHV and THC, wherein the ratio of THCV:THC byweight is between about 10:1 and about 1:10.5. Pharmaceutical composition according to clause 4, wherein the ratioof THCV:THC by weight is between about 1:5 and about 5:1.6. Pharmaceutical composition according to clause 4, wherein the ratioof THCV:THC by weight is about 10:1 and about 1:10.7. Pharmaceutical composition according to clause 4, wherein the ratioof THCV:THC by weight is between about 1:1 and about 10:1.8. Pharmaceutical composition according to clause 3, wherein THCV isadministered separately, simultaneously or sequentially to THC.9. Pharmaceutical composition according to clause 1, wherein thecomposition further comprises CBG, CBND or a mixture thereof.10. Pharmaceutical composition according to clause 5, wherein thecomposition comprises further comprises a mixture of CBG and CBND,wherein the ratio of CBG:CBND by weight is between about 10:1 and about1:10.11. Pharmaceutical composition according to clause 1, wherein thecomposition is a unit dosage form comprising less than or equal to 120mg of THCV.12. Pharmaceutical composition according to clause 1, wherein thecomposition is a unit daily dosage form comprising less than or equal to150 mg of THC.13. Pharmaceutical composition according to clause 1, wherein thecomposition is packaged for delivery in a titratable dosage form.14. Pharmaceutical composition according to clause 1, wherein thecomposition is a gel, a gel spray, a tablet, a liquid, a capsule, in aform suitable for vaporization or in a form suitable for nebulisation.15. Pharmaceutical composition according to clause 1, wherein theoverweight is associated with obesitas.16. Method for treating a mammal suffering from overweight or a relateddisorder, wherein a pharmaceutical composition according to clause 1 isadministered to said mammal.

1. A composition comprising a tetrahydrocannabivarin (THCV) wherein thecomposition further comprises cannabigerol (CBG) or cannabinodiol (CBND)or a mixture thereof for use in the prevention and/or treatment ofoverweight.
 2. The composition according to claim 1, wherein thetetrahydrocannabivarin (THCV) is selected from the group consisting ofΔ9-tetrahydrocannabivarin (THCV), Δ8-tetrahydrocannabivarin (Δ8-THCV),and one or more mixtures thereof.
 3. The composition of claim 1, whereinthe composition further comprises tetrahydrocannabinol (THC).
 4. Thecomposition of claim 3, wherein the ratio of THCV:THC by weight isbetween about 10:1 and about 1:10.
 5. The composition of claim 4,wherein the ratio of THCV:THC by weight is between about 1:5 and about5:1.
 6. The composition of claim 4, wherein the ratio of THCV:THC byweight is between about 1:1 and about 10:1.
 7. The composition of claim1, wherein THCV is administered separately, simultaneously orsequentially to THC.
 8. The composition of claim 7, wherein the ratio ofCBG:CBND by weight is between about 10:1 and about 1:10.
 9. Thecomposition of claim 8, wherein the mixture comprisestetrahydrocannabivarin (THCV), tetrahydrocannabinol (THC), Cannabigerol(CBG) and Cannabinodiol (CBND) in a ratio by weight of THCV:THC ofbetween about 1:5 and about 5:1 and CBG:CBND of between about 10:1 andabout 1:10.
 10. The composition of claim 1, wherein the composition is aunit dosage form comprising less than or equal to 120 mg of THCV. 11.The composition of claim 3, wherein the composition comprisestetrahydrocannabinol (THC) and is a unit daily dosage form comprisingless than or equal to 150 mg of THC.
 12. The composition of claim 1,wherein the composition is packaged for delivery in a titratable dosageform.
 13. The composition of claim 1, wherein the composition is a gel,a gel spray, a tablet, a liquid, a capsule, in a form suitable forvaporization or in a form suitable for nebulization.
 14. The compositionof claim 1, wherein the use in the prevention and treatment ofoverweight is the use in the prevention and treatment of overweightassociated with obesity.
 15. The composition of claim 1, wherein thecomposition comprises less than 0.10 wt. % of cannabichromene (CBC)and/or cannabinol (CBN) based on the weight of THCV.